The long-term objective is to clarify at the chemical level the fate of selenium, its functions as an essential element, and its modifying effects on toxicants or carcinogenesis. There is great interest in supplementing the human diet with selenium to correct nutritional deficiencies or to modify the carcinogenic process. There is rather limited knowledge about forms of selenium in tissues, metabolic formations, and detoxification or excretory products. There are striking biochemical effects of selenium deficiency which cannot be explained on the basis of known biochemical functions for selenium. This study follows up important discoveries made during the previous project in regard to Se metabolism and its functions. The first objective is to isolate a monomethylated form of selenium that is a major unidentified urinary metabolite at physiological levels of selenium intake. The second objective explores the mechanism for selenium demethylation, a new concept in selenium metabolism that was solidly established in our previous project. The hypothesis to be tested is that trimethylselenomium will serve as a methyl donor, undergoing enzyme-catalyzed demethylation in the presence of a specific methyl acceptor. Furthermore, methionine status of the animal is postulated to affect the availability of the acceptor or the activity of the enzyme. These studies break new ground in regard to the fate and function of trimethylselenomium, which has been regarded until now as a dead-end excretory metabolite. Selenium and iodine nutrition and metabolism will be explored, because we believe that insufficient attention has been paid to possible physiologically-significant interactions of these elements. Particular emphasis will be directed toward the basis for the markedly decreased rate of thyroxin deiodination to active hormone (T3) in Se deficient rat tissues, which we and others have recently demonstrated. Coenzyme Q, an important cofactor for energy production has been reported to be decreased in hearts of Se-deficient animals. The effect of Se deficiency on this cofactor and related aspects of lipid metabolism will be studied, in view of the possible significance to the etiology of the Se-responsive myopathy, Keshan disease, in humans.